The Association Between MTOR And Ulcerative Colitis

BackgroundInflammatory bowel disease(IBD)is a chronic non-specific gastrointestinal inflammatory disease,consists of ulcerative colitis(UC)and Crohn’s disease(CD).And ulcerative colitis is one of the recognized precancerous lesions,The overall incidence rate of colorectal cancer in UC patient was 3/1000 person years duration.Its incidence rate has been increasing year by year in China.Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells,dysregulation of signal transduction pathways,elevated mucosal T cell activation,increased production of proinflammatory cytokines,and enhanced leukocyte infiltration into colonic interstitium.Mammalian target of rapamycin(mTOR)is a serine-threonine protein kinase that regulates protein synthesis,cell growth,and cell proliferation in response to growth factors and nutrients.More recently,accumulating evidence causally links increased mTOR activity to heightened inflammatory responses.The inhibitor of mTOR——rapamycin,was firstly used for immune rejection in organ transplant patients.Walter Reinisch and his colleagues reported that the safety and tolerability of everolimus(6 mg/day)in patients with active CD were comparable to azathioprine.However,it is rare to treat UC patients with mTOR inhibitors.We will observe whether the expression of mTOR is related to the activity of ulcerative colitis firstly;then,we will observe the role of mTOR on the development of ulcerative colitis in mice model.This research is to investigate the association between mTOR and ulcerative colitis.MethodsThe samples of 55 cases of UC tissues were collected.By using immunohistochemistty,the expression of mTOR was detected.Then,we established the mice model of ulcerative colitis and detected the expression of mTOR in the model.Then the mice was treated with the everolimus to probe the efficacy of inhibitor of mTOR.Chronic colitis was induced in mice by giving 2%DSS(molecular mass 30-40 kDa)for 1 week then water for 2 weeks for two cycles.For each mouse,weight and rectal bleeding were determined every day following the introduction of DSS.To probe the efficacy of everolimus,a group of ten mice were given daily gastric perfusion of 3 mg/kg everolimus at the beginning of the experiment.Another group of ten mice were given daily gastric perfusion of the same volume of water.At the end of the experiment,the mice were killed and colon tissues were collected.Results:The results of IHC indicates mTOR is overexpressed in the patients with UC.And in different stages of ulcerative colitis,the expression of mTOR is progressive.In the dextran sulfate sodium(DSS)model of colitis,1)macroscopic colon observations demonstrated that everolimus significantly reversed DSS-induced shortening of the colon;2)histological analyses of colonic tissues revealed that everolimus distinctly attenuated DSS induced edema,prominently diminished the leukocyte infiltration in the colonic mucosa,and resulted in protection against DSS-induced crypt damage.Conclusion:Collectively,these results indicate that mTOR is overexpressed in UC.Everolimus preventive treatment of established colitis in mice ameliorated the colitis.